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Journal of Virology, September 1998, p. 7367-7373, Vol. 72, No. 9
Laboratory of Microbiology, Department of
Disease Control, Graduate School of Veterinary Medicine, Hokkaido
University, Sapporo 060, Japan1;
Departamento de Virologia, Instituto de Microbiologia, UFRJ,
Rio de Janeiro, RJ 21941-590, Brazil2;
Biochemisches Institut, University of Kiel, 24098 Kiel,
Germany3;
Department of Pathology
and Laboratory Medicine, UCLA School of Medicine, Los Angeles,
California 90024-17324;
Department
of Virology and Molecular Biology, St. Jude Children's Research
Hospital, Memphis, Tennessee 381015;
Department of Virology, Istituto Superiore di Sanita, Rome,
Italy6;
Cytel, Inc., and Department
of Chemistry, Scripps Research Institute, La Jolla, California
920377; and
Department of Pathology,
University of Tennessee, Memphis, Tennessee 381638
Received 17 March 1998/Accepted 19 May 1998
Genetic and biologic observations suggest that pigs may serve as
"mixing vessels" for the generation of human-avian influenza A
virus reassortants, similar to those responsible for the 1957 and 1968 pandemics. Here we demonstrate a structural basis for this hypothesis.
Cell surface receptors for both human and avian influenza viruses were
identified in the pig trachea, providing a milieu conducive to viral
replication and genetic reassortment. Surprisingly, with continued
replication, some avian-like swine viruses acquired the ability to
recognize human virus receptors, raising the possibility of their
direct transmission to human populations. These findings help to
explain the emergence of pandemic influenza viruses and support the
need for continued surveillance of swine for viruses carrying avian
virus genes.
This century has seen the emergence
of four pandemic strains of human influenza virus: the Spanish
influenza virus of 1918, the Asian influenza virus of 1957, the Hong
Kong influenza virus of 1968, and the Russian influenza virus of 1977. The pandemic viruses isolated in 1957 and 1968 were reassortants
possessing genes of both human and avian viruses. Avian virus genes
encoding the hemagglutinin (HA), neuraminidase, and PB1 proteins were
introduced into the 1957 strain, while the 1968 strain acquired only
the avian virus HA and PB1 genes (20, 27, 37).
Avian influenza viruses replicate less efficiently in humans
(1) and in other primates (more than 100-fold)
(29). Although immunity to currently circulating human H1
and H3 viruses may explain the poor replication of these subtypes of
avian viruses in human hosts, it does not account for the limited
replication of avian viruses with other subtypes not found in humans
(i.e., H4, H6, H9, and H10) (1). Similarly, human viruses do
not replicate efficiently in waterfowl when introduced by natural
routes (18). Therefore, although avian influenza viruses can
be directly transmitted to humans as indicated by a recent incident in
Hong Kong (9, 39), the probability of these viruses becoming
established in human populations is low, thereby limiting opportunities
for the generation of human-avian reassortant viruses in these host
animals. How, then, does one explain the apparent breach of this host
range restriction during the generation of pandemic influenza viruses? Scholtissek et al. (36) proposed that pigs may serve as
"mixing vessels" for the production of reassortant influenza
viruses. Indeed, a variety of avian and human influenza viruses
replicate efficiently in pigs upon experimental infection (17,
23). Results of phylogenetic and epidemiologic analyses indicate
that avian and human viruses have also been transmitted to pigs in nature (12, 38) and that they have reassorted in pigs
(7) and been transmitted to humans (8). Despite
this considerable body of circumstantial evidence, the molecular basis
for human-avian viral gene reassortment in pigs remains unknown.
Although influenza A viruses uniformly recognize cell surface
oligosaccharides with a terminal sialic acid, their receptor specificity varies. Most avian influenza viruses preferentially bind to
the N-acetylneuraminic acid- Viruses.
The influenza A viruses used in this study (Table
1) were maintained in repositories at St.
Jude Children's Research Hospital in Memphis, Tenn., the Istituto
Superiore di Sanita in Rome, Italy, and the Graduate School of
Veterinary Medicine of Hokkaido University in Sapporo, Japan.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Molecular Basis for the Generation in Pigs of
Influenza A Viruses with Pandemic Potential
ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
2,3-galactose
(NeuAc2,3Gal) linkage on sialyloligosaccharides, while human
influenza viruses prefer the NeuAc2,6Gal linkage (32,
33). However, very little is known about the
sialyloligosaccharide structures at viral replication sites in pigs or
in other common hosts. Since the presence or absence of viral
species-specific receptors on host cells would have a key role in
generating viruses with pandemic potential, we sought to identify the
types of sialyloligosaccharides at the replication sites of influenza
viruses in ducks and pigs and to test their suitability for binding
various avian and swine viruses. The results we report help to clarify
how avian influenza A viruses could overcome normal host range
barriers and infect human populations.
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
TABLE 1.
Receptor specificities of H1N1 influenza
A virusesa
Nucleotide sequencing. Molecular cloning, nucleotide sequencing, and nucleotide analysis were performed as previously described (20).
Receptor specificity analysis. The receptor specificity of viruses was determined by hemagglutination tests, using derivatized erythrocytes at room temperature (32). In this assay, the titration of end points was performed after 30 min and 1 h, with essentially no differences in results.
Immunologic detection of NeuAc2,3Gal and NeuAc2,6Gal
linkages.
The colons of 4-week-old F1 hybrid ducks
(Pekin, Anas platyrhynchos domesticos, and mallard,
Anas platyrhynchos platyrhyncos) and the tracheas of
70-day-old F1 hybrid pigs (Landrace and Durock lines) were
collected immediately after exsanguination by cardiac puncture, rinsed
with phosphate-buffered saline (PBS; pH 7.2), and cut into cubes (3 mm3 each). The tissue blocks were then embedded in OCT
compound (Miles Inc., Indianapolis, Ind.) and frozen in liquid
nitrogen. Tissue sections (6 µm each) were cut from the blocks with a
microtome cryostat, air dried, and fixed for 15 min with cold acetone
before immunostaining. The presence or absence of NeuAc2,3Gal
and NeuAc2,6Gal linkages in these organs was determined with
linkage-specific lectins (glycan differentiation kit; Boehringer
Mannheim Biochemicals). Briefly, each section was incubated with 50 µl of digoxigenin (DIG)-labeled Sambucus nigra (1 µg/ml;
specific for NeuAc2,6Gal) or Maackia amurensis (5 µg/ml; specific for NeuAc2,3Gal) agglutinin for 1 h
at room temperature. After three washes with cold PBS, the S. nigra and M. amurensis agglutinin-exposed sections were incubated with fluorescein- and rhodamine-conjugated anti-DIG antibody
(Boehringer Mannheim Biochemicals), respectively, for 1 h at
room temperature. After three washes with cold PBS, the tissue sections
were mounted on slides in buffered glycerol (pH 9.0) for observation
with a fluorescence microscope (BH-RFL; Olympus Optics, Tokyo, Japan)
equipped with a dark-field condenser and UV excitation
capability. Control slides were incubated with PBS instead of lectin.
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RESULTS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Pig trachea contains receptors for both avian and human
viruses.
Because avian and human influenza viruses show different
receptor preferences, NeuAc2,3Gal versus NeuAc2,6Gal
(32, 33), and epithelial cells lining human trachea possess
mainly the latter sialyloligosaccharide (11), we considered
that one of the determinants of the replicative potential of such
viruses in different hosts might be the sialic acid-galactose
linkage present on sialyloligosaccharides. Using
linkage-specific lectins, we examined the epithelial cells of
duck intestine and pig trachea for NeuAc2,3Gal and
NeuAc2,6Gal. Duck intestine was chosen for these experiments
because avian influenza viruses replicate well in this site and only
marginally in duck trachea (24). Duck intestine showed a
strong reaction with M. amurensis lectin (specific for
NeuAc2,3Gal) but not with S. nigra lectin (specific
for NeuAc2,6Gal), whereas pig trachea reacted with both linkages
(Fig. 1). These results, together with the findings of Couceiro et al. (11), using the same lectin method, that ciliated epithelial cells in human trachea contain NeuAc2,6Gal but not NeuAc2,3Gal, suggest that the lack of
a suitable receptor accounts for the inefficient replication
of human viruses in duck intestine and of avian viruses in humans. Moreover, detection of both linkages in pig trachea provides a molecular basis for efficient replication of human and avian influenza viruses in this host (17, 23).
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Changes in receptor specificity during the adaptation of
avian viruses to pigs.
Three types of influenza viruses are
circulating in pigs: classic H1N1, maintained in this species for more
than 60 years; human-like H3N2, present in pigs since 1969 (26); and avian-like H1N1, introduced into European pigs in
1979 (35). Since pig trachea contains both the
NeuAc2,6Gal and the NeuAc2,3Gal linkages (Fig. 1), we
were uncertain whether the avian-like H1N1 virus had retained its
preference for NeuAc2,3Gal after the parental avian strain was
introduced into the pig population. A receptor specificity analysis
indicated that all of the human and classic swine viruses
preferentially recognize NeuAc2,6Gal, whereas most avian
viruses prefer NeuAc2,3Gal (Table 1), as
previously reported (32, 33). One avian virus,
A/mallard/Alberta/740/80, recognized both NeuAc2,3Gal and
NeuAc2,6Gal. Other avian viruses with dual receptor
specificities have been reported (14, 32). Surprisingly, the avian-like swine viruses showed a shift in receptor
specificity over time. Viruses isolated from European pigs up
to 1984 recognized both sialic acid-galactose linkages,
whereas those isolated after 1985 recognized only
NeuA c2,6Gal (Table 1). A/Swine/Netherlands/12/85 recognized NeuAc2,6Gal-containing
erythrocytes appreciably less efficiently than those with
native linkages, for unknown reasons. Nonetheless, the shift in
receptor specificity suggests a mechanism that would allow avian
viruses to replicate in humans efficiently.
Amino acid residues responsible for the shift in receptor
specificity among avian-like swine viruses.
To understand
the receptor specificity conversion that occurred in avian-like
swine viruses at some point between 1984 and 1985, we first determined
the phylogenetic relationships among the H1 HAs (Fig.
2). The analysis established that the HA
of avian-like swine viruses was introduced from birds once and then
evolved thereafter, as did other genes of these viruses (6).
Comparison of the amino acid sequences of the HA molecules (Fig.
3 and Table 2) showed that an amino acid change
at residue 142 (145 in the H3 numbering system) was the only
substitution that occurred between 1983 and 1985 and was
associated with loss of NeuAc2,3Gal recognition. Avian-like swine viruses isolated in 1985 or later
(A/swine/Netherlands/12/85, A/swine/Italy- Vir/671/87, A/swine/Germany/3/91, and A/swine/Schleswig- Holstein/1/92)
contained Leu at this position, whereas those isolated earlier had
different amino acids: A/swine/Arnsberg/79 and
A/swine/Netherlands/80, Ser; A/swine/Germany/2/81, His; and
A/swine/Belgium/83, Arg. Residue 142 (145 in the H3 numbering system)
is located on the loop of the HA near the receptor-binding pocket (Fig.
4), supporting our contention that a
mutation at this position may have contributed to a shift in receptor
specificity.
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DISCUSSION |
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We have demonstrated that pig trachea contains receptors for both
human and avian influenza viruses, providing a milieu conducive to the
replication, and hence the genetic reassortment, of these viruses.
Moreover, with continued replication in pigs, the avian viruses appear
to undergo a shift in their receptor specificity to NeuAc2,6Gal
linkages exclusively. These observations suggest at least two
mechanisms, both dependent on HA-receptor interactions, that would
permit pigs to serve as intermediate hosts for the generation of
pandemic influenza viruses (Fig. 5). In
one, avian and human viruses would reassort in classical fashion,
giving rise to a hybrid strain with pandemic potential (Fig.
5A). In the other, an avian virus would acquire the ability to bind
efficiently to human cell surface receptors so that it could be readily
transmitted to a human host without a requirement for genetic
recombination (Fig. 5B). These models may not be mutually exclusive.
Quite possibly, an avian virus could combine with a human virus before
or after becoming adapted to the NeuAc2,6Gal linkage, resulting
in a reassortant with enhanced proliferative capacity.
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Circumstantial evidence (7, 8, 36) favors the involvement of pigs in genetic reassortment; however, direct transmission of avian viruses to humans does occur, as exemplified by the recent incident in Hong Kong (9, 39), so that reassortment in humans (Fig. 5C) or adaptation to recognize receptors in humans (Fig. 5D) cannot be discounted. With the rarity of human influenza pandemics, it is difficult to predict which of the models in Fig. 5 is more likely to generate a potentially hazardous virus. In addition to the Hong Kong H5N1 outbreak, avian viruses have been transmitted directly from birds to a variety of mammals, including seals, mink, and horses (13, 16, 25).
What types of selective pressure drive the shift in receptor
specificity of avian-like swine influenza viruses from both
NeuAc2,3Gal and NeuAc2,6Gal to NeuAc2,6Gal
exclusively? One possibility is that the NeuAc2,6Gal linkage is
more abundant than NeuAc2,3Gal on the epithelial cells of pig
trachea, thus providing a replicative advantage for viruses that
recognize the former receptor. Alternatively, glycoproteins
containing NeuAc2,3Gal may exist at viral replication sites in pigs, serving as receptor analog inhibitors.
Detection of the NeuAc2,3Gal linkage in mucin from human
trachea (11) supports this suggestion.
One avian virus in our study, A/mallard/Alberta/740/80, recognized both
NeuAc2,3Gal and NeuAc2,6Gal, consistent with reports by
others (10, 31, 32). In a natural setting, would avian viruses with this dual binding capacity be the ones transmitted to
pigs? Although a number of avian viruses have been shown to replicate
in pigs in experimental infection (17, 23), their receptor
specificities are largely unknown. Of the avian viruses we have tested,
most recognize only the NeuAc2,3Gal linkage and those tested for
replicative activity in pigs have multiplied efficiently, suggesting
that a lack of affinity for the NeuAc2,6Gal linkage would not
preclude natural transmission of an avian virus to pigs.
A single substitution at position 145 (H3 numbering), located on the
loop near the receptor-binding site of the HA molecule, appears
responsible for the inability of avian-like swine viruses isolated
after 1984 to bind to NeuAc2,3Gal linkages. A mutation at the
same position was also identified in variant human influenza A viruses
during their adaptation in eggs (28); however, the receptor
specificity change in the avian-like swine viruses described here is
not likely an artifact of egg adaptation, as classic swine viruses such
as A/swine/Iowa/15/30 (H1N1) have been passaged many times in eggs
without loss of NeuAc2,6Gal specificity (Table 1). Also,
swine viruses directly isolated in Madin-Darby canine kidney
(MDCK) cells or in eggs show identical receptor specificities (21a). The precise mechanism by which this mutation causes a shift in receptor specificity is unknown and will likely remain so
until the crystal structure of the mutant HA is determined.
The molecular features of the HA that influence the virulence of avian influenza viruses in birds are well characterized (3, 4, 21, 22) and have been used successfully to predict whether an emerging influenza virus poses a threat to large concentrations of poultry. Progress in identifying viruses with pandemic potential in human populations has been less impressive. None of the avian-human reassortants identified since 1968 (7), or any of the avian-like swine viruses, has produced a global outbreak of influenza in humans. This suggests that the generation of pandemic strains of influenza A virus is a complex process, requiring critical combinations of avian and human viral genes or mutations beyond those affecting the HA molecule. Indeed, multiple genes affect the interspecies transmission of influenza viruses (18, 23, 36). One could also argue that immunity to H1 HAs in human populations would protect against infection by the H1N1 avian-like swine viruses. However, since human H1 viruses and avian-like swine viruses show appreciable differences in antigenicity (15), it will be necessary to evaluate the latter in primates before making conclusions as to their replicative capacity in humans.
Many new viral pathogens have emerged in humans (e.g., human immunodeficiency virus, influenza A viruses, Ebola virus, hantavirus, monkeypox virus, and Borna disease virus). Learning the precise molecular changes that allow these agents to cross host species barriers is essential to developing an effective means of prevention. The evidence we present supports the role of pigs as a source of potentially hazardous influenza A viruses, arising through classical genetic reassortment or a novel adaptation to human virus receptors or perhaps through both mechanisms. Thus, continued intensive monitoring of swine populations for avian-like influenza viruses should be an integral part of global health planning.
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ACKNOWLEDGMENTS |
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We thank Krisna Wells for excellent technical assistance, Clayton Naeve and the St. Jude Children's Research Hospital Molecular Resource Center for preparation of oligonucleotides, Patricia Eddy and the Molecular Biology Computer Facility for computer support, Yuko Kawaoka for illustration, and John Gilbert for scientific editing.
This work was supported by Public Health Service research grants AI-29680 and AI-33898 from the National Institute of Allergy and Infectious Diseases, Cancer Center Support (CORE) grant CA-21765, and the American Lebanese Syrian Associated Charities (ALSAC).
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FOOTNOTES |
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* Corresponding author. Present address: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Dr. West, Madison, WI 53706. Phone: (608) 265-4925. Fax: (608) 265-5622. E-mail: kawaokay{at}svm.vetmed.wisc.edu.
Present address: Faculty of Agriculture, Tottori University,
Koyama-cho, Tottori, Japan.
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Introduction
Materials & Methods
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Discussion
References
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Journal of Virology, September 1998, p. 7367-7373, Vol. 72, No. 9
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